Carbene porphyrins and carbene porphyrinoids, methods of preparation and uses thereof

ABSTRACT

The present invention includes novel N-heterocyclic carbene substituted porphyrins and porphyrinoids. The invention also includes complexes of metals and N-heterocyclic carbene substituted porphyrins and porphyrinoids. The invention further includes N-heterocyclic carbene substituted porphyrins and porphyrinoids, and metal complexes of N-heterocyclic carbene substituted porphyrins and porphyrinoids that also includes a targeting moiety or group. The compositions of the present invention are useful in the fields of diagnosis and treatment of many medical ailments.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US01/50754, filed Nov. 9, 2001, which claims the benefit of U.S.Provisional Application No. 60/247,326, filed Nov. 10, 2000.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel compositions of matter. Thepresent invention more particularly relates to ligands, complexes of theligands with metals to form ligand-metal complexes, processes forpreparation of the ligands and ligand-metal complexes and uses thereof.

BACKGROUND OF THE INVENTION

Porphyrins and related tetrapyrrolic macrocycles have application invarious medical procedures for the diagnosis and treatment of disease.

Magnetic Resonance Imaging (MRI) is a process in which a particularobject to be viewed is exposed to a radio frequency while in thepresence of a varying magnetic field. In general, MRI utilizes contrastagents to produce cross-sectional images for medical diagnosis. The useof contrast agents allows one to differentiate the target tissue ofinterest from the surrounding tissue in the image. The use of contrastagents with MRI, however, suffers from several limitations. For example,one major limitation of the use of certain contrast agents is thedisassociation of the metal from the metal complex of the contrastagent, which can leave toxic levels of metals within the body of anpatient.

Positron Emission Tomography (PET) is a type of tomography produced bythe detection of gamma rays emitted from tissues after theadministrations of a natural biochemical substance into whichpositron-emitting isotopes have been incorporated. A major limitation ofthe use of certain contrast agents with PET is the disassociation of theradioactive isotopes from the agent, which can leave toxic levels ofradioactive elements within the body of an patient.

Porphyrins and related tetrapyrrolic macrocycles also have applicationin the field of Photodynamic Therapy (PDT). PDT is a technique thatutilizes photosensitive compounds that have a selective affinity fordiseased tissue and which accumulate in diseased tissue to a greaterextent than in normal tissue. PDT involves the localization of aphotosensitizing agent in or near a diseased target tissue within thebody. The photosensitive compound, upon illumination and in the presenceof oxygen, produces cytotoxic species of oxygen such as singlet oxygenor oxygen radicals, which destroy the diseased target tissue. The PDTtechnique provides a greater degree of selectivity or specificity notcurrently achievable with current methods of chemotherapy.

Heterocyclic carbenes have been found to be useful as complexing ligandsfor a wide variety of metals to produce corresponding ligand-metalcomplexes having good thermal and chemical stability.

The synthesis of transition metal complexes of imidazol-2-ylidenes, alsoknown as N-heterocyclic carbenes, was first pioneered by Ofele andWanzlick in 1968 and is a very active area of research today. Thesynthesis of free isolable N-heterocyclic carbenes and theircomplexation with transition metals was first reported by Arduengo in1991. It is not always convenient, however, to synthesize complexes fromfree carbenes and transition metals. A recent advance is the use ofsilver bis(carbene) complexes as carbene transfer reagents.

A process for the preparation of heterocyclic carbenes is described inU.S. Pat. No. 6,025,496 to Hermann et al.

Therefore, the needs exists in the art to develop improved ligands andligand-metal complexes for diagnostic and therapeutic applications.

SUMMARY OF THE INVENTION

The present invention, in one embodiment, provides a composition ofmatter comprising a N-heterocyclic carbene substituted porphyrins.

The present invention, in another embodiment, provides a composition ofmatter comprising a N-heterocyclic carbene substituted porphyrinoids.

The present invention, in another embodiment, further provides a complexcomprising a N-heterocyclic carbene substituted porphyrin ligand and ametal bonded to said ligand.

The present invention, in another embodiment, further provides a complexcomprising a N-heterocyclic carbene substituted porphyrinoid ligand anda metal bonded to said ligand.

The present invention, in another embodiment, further provides a methodfor preparing N-heterocyclic carbene substituted porphyrins.

The present invention, in another embodiment, further provides a methodfor preparing N-heterocyclic carbene substituted porphyrinoids.

The present invention, in another embodiment, further includes a methodfor providing a complex comprising a N-heterocyclic carbene substitutedporphyrin ligand and a metal bonded to said ligand.

The present invention, in another embodiment, further provides a methodfor preparing a complex comprising a N-heterocyclic carbene substitutedporphyrinoid ligand and a metal bonded to said ligand.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention provides novel macrocycles suitable for detecting(diagnosing) and treating target tissues, cells and pathogens. Thecompositions of the present invention possess novel chelating propertiesand cavity sizes, which enable them to stabilize metals in a range oftypical and a typical oxidation states and coordination geometries. Thecompositions of the present invention find particular application inmedical applications, such as Magnetic Resonance Imaging (MRI), PositronEmission Tomography (PET), Photodynamic Therapy (PDT), although thecompositions have a wide variety of other applications.

In on embodiment, the present invention relates to N-heterocycliccarbene substituted porphyrins. That is, the compositions of the presentinvention are substituted porphyrins having at least one pyrrole ring ofthe porphyrin ring replaced by a N-heterocyclic carbene group. In otherembodiments of the present invention, in addition to having at least onepyrrole group of the porphyrin ring replaced with a N-heterocycliccarbene group, at least one of the pyrrole groups of the porphyrin ringmay also be replaced with a pyridine ring.

As those having ordinary skill in the art know, the term “porphyrin”refers to any of several physiologically active nitrogen-containingcompounds. In general, a porphyrin compound includes four pyrrole rings,each ring containing a nitrogen atom and where two of the pyrrole ringsalso include replaceable hydrogen atoms. A porphyrin may be generallyrepresented by the following formula:

The synthesis of porphyrin isomers is known, where the nitrogen atom ofone of the pyrrole rings that binds to a central metal atom to form ametal complex is replaced with a carbon atom. These porphyrin isomers,referred to as carbaporphyrins, N-confused porphyrins, or invertedporphyrins, may be represented by the following formula:

N-confused porphyrins as shown in Formula II, above, have a multivalentnature as a metal ligand and are known to complex with metal atoms inthe +2 and +3 oxidation states to form neutral square planar complexes,as shown in the following formulas:

Doubly N-confused porphyrins may also be synthesized and are able toform metal complexes with metals in the +3 oxidation state, as shown bythe following formula:

The N-heterocyclic carbene substituted porphyrins and porphyrinoids ofthe present invention may be broadly represented by the followingformulas:

where formulas VI and VII, A-D may be the same or different and may beselected from one of the following formulas, with the proviso that atleast one of A-D is N-heterocyclic carbene:

where R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogenand organic groups including alkyl, cyclo alkyl, substituted cycloalkyl,alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl,substituted aryl, arylalkyl, alkylaryl, and alkoxy, where each grouppreferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms.

The N-heterocyclic carbene substituted expanded porphyrins and expandedporphyrinoids of the present invention may be broadly represented by thefollowing formulas:

where formulas XI and XII, A-D may be the same or different and may beselected from one of the following formulas, with the proviso that atleast one of A-D is N-heterocyclic carbene:

where R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogenand organic groups including alkyl, cyclo alkyl, substituted cycloalkyl,alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl,substituted aryl, arylalkyl, alkylaryl, and alkoxy, where each grouppreferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms; andwhere Ay, By, Cy and Dy is 1 or greater, with the proviso that at leastone of Ay, By, Cy and Dy is at least 2.

The following examples are set forth to describe the N-heterocyclicsubstituted carbene porphyrin and porphyrinoid compositions of thepresent invention in further detail. The examples are intended to beillustrative, and should not be construed as limiting the scope of thepresent invention in any manner.

In one embodiment, at least one pyrrole ring of the porphyrin isreplaced with a N-heterocyclic carbene group. The composition of thisembodiment may be represented by any one of the following formulas:

In another embodiment, two of the pyrrole rings of the porphyrincompound have been replaced with N-heterocyclic carbene groups. Thecompounds having two pyrrole rings replaced with N-heterocyclic carbenegroups may be represented by any one of the following formulas:

In another embodiment, three pyrrole rings of the porphyrin compoundhave been replaced with N-heterocyclic carbene groups. The compoundshave three N-heterocyclic carbene groups may be represented by thefollowing formula:

In another embodiment, four pyrrole rings of the porphyrin compound havebeen replaced with N-heterocyclic carbene groups. The compositionshaving four pyrrole rings of the porphyrin compound have been replacedwith N-heterocyclic carbene groups may be represented by the followingformula:

In another embodiment, the present invention provides compositionswherein at least one of the pyrrole rings of the porphyrin compound isreplaced with a N-heterocyclic carbene group and at least one otherpyrrole rings is replaced with a pyridine ring. The compositions havingat least one of the pyrrole rings of the porphyrin compound is replacedwith a N-heterocyclic carbene group and at least one other pyrrole ringis replaced with a pyridine ring may be represented by any one of thefollowing formulas:

While the present invention has been described with respect to thesubstitution of porphyrins with at least one N-heterocyclic carbenegroup, the compositions and processes described herein also encompassother tetrapyrrolic macrocycles, such as the larger aromaticpyrrole-containing systems, referred to as “expanded porphyrins”.

The term expanded porphyrin and expanded porphyrinoids refer to thoselarge aromatic pyrrole-containing systems that generally contain morethan four rings that constitute the macrocycle. As for the porphyrinsystems, at least one pyrrole ring of an expanded porphyrin or expandedporphyrinoid can be replaced with a N-heterocyclic carbene group to forma N-heterocyclic carbene expanded porphyrin or a N-heterocyclic carbenesubstituted expanded porphyrinoid.

In one embodiment, at least one pyrrole ring of the expanded porphyrinsapphyrin may be replaced by a N-heterocylic carbene group. Sapphyrin isrepresented by the following formula:

Compounds of the present invention having at least one pyrrole ring ofthe expanded porphyrin sapphyrin replaced by a N-heterocylic carbenegroup are represented by the following formulas:

In another embodiment, the present invention provides compositionshaving at least two pyrrole rings of the expanded porphyrin sapphyrinreplaced with N-heterocyclic carbene groups. Compounds of the presentinvention having at least two pyrrole rings of the expanded porphyrinsapphyrin replaced by N-heterocylic carbene groups are represented bythe following formulas:

In another preferred embodiment, at least one pyrrole ring of theexpanded porphyrin pentaphyrin is replaced by a N-heterocylic carbenegroup. The expanded porphyrin pentaphyrin is represented by thefollowing formula:

In one embodiment, at least one pyrrole ring of the expanded porphyrinpentaphyrin has been replaced with a N-heterocyclic carbene group.Compositions of the present invention having at least one pyrrole ringof the expanded porphyrin pentaphyrin has been replaced with aN-heterocyclic carbene group are represented by the following formulas:

In another embodiment, at least two pyrrole rings of the expandedporphyrin pentaphyrin has been replaced with a N-heterocyclic carbenegroups. Compositions of the present invention having at least twopyrrole rings of the expanded porphyrin pentaphyrin has been replacedwith a N-heterocyclic carbene groups is represented by the followingformula:

In another preferred embodiment, at least one pyrrole ring of theexpanded porphyrin hexaphyrin is replaced by a N-heterocylic carbenegroup. Hexaphyrin is represented by the following formula:

In one embodiment, at least one pyrrole ring of the expanded porphyrinhexaphyrin is replaced by a N-heterocyclic carbene group. Compositionsof the present invention at least one pyrrole ring of the expandedporphyrin hexaphyrin is replaced by a N-heterocyclic carbene group arerepresented by the following formula:

In another embodiment, at least two pyrrole rings of the expandedporphyrin hexaphyrin is replaced by N-heterocyclic carbene group.Compositions of the present invention at least two pyrrole rings of theexpanded porphyrin hexaphyrin are replaced by N-heterocyclic carbenegroups are represented by the following formulas:

In another embodiment, at least three pyrrole rings of the expandedporphyrin hexaphyrin are replaced by N-heterocyclic carbene groups.Compositions of the present invention at least three pyrrole rings ofthe expanded porphyrin hexaphyrin are replaced by N-heterocyclic carbenegroups are represented by the following formula:

While the present invention has been illustrated in further detail withreference to tetrapyrrolic porphyrin and the expanded porphyrinssapphryin, pentaphyrin and hexaphyrin, it should be noted that thepresent invention is not limited to those expanded porphyrins describedherein. The present invention, therefore, includes other expandedporphyrins in which at least one pyrrole ring is replaced byN-heterocyclic carbene groups.

The N-heterocyclic carbene substituted porphyrins and N-heterocycliccarbene substituted porphyrinoids of the present invention are useful asligands to form ligand-metal complexes with a selected or desired metalatom or atoms.

The metal complexes of the present invention include a N-heterocycliccarbene substituted porphyrin or N-heterocyclic carbene substitutedporphyrinoid and at least one metal atom bonded to the N-heterocycliccarbene substituted porphyrin or N-heterocyclic carbene substitutedporphyrinoids. The metal complexes of this embodiment may be broadlyrepresented by the following formulas:

where for formulas XXXXVI and XXXXVII, A-D may be the same or differentand may be selected from one of the following formulas, with the provisothat at least one of A-D is N-heterocyclic carbene:

where R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogenand organic groups including alkyl, cyclo alkyl, substituted cycloalkyl,alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl,substituted aryl, arylalkyl, alkylaryl, and alkoxy, where each grouppreferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms; andwhere M is a metal.

The metal complexes of this embodiment, which in clued at least onemetal atom bonded to a N-heterocyclic carbene substituted expandedporphyrin or expanded porphyrinoids may be broadly represented by thefollowing formulas:

where formulas XXXXVIII and XXXXIX, A-D may be the same or different andmay be selected from one of the following formulas, with the provisothat at least one of A-D is N-heterocyclic carbene:

where R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogenand organic groups including alkyl, cyclo alkyl, substituted cycloalkyl,alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl,substituted aryl, arylalkyl, alkylaryl, and alkoxy, where each grouppreferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms; andwhere Ay, By, Cy and Dy is 1 or greater, with the proviso that at leastone of Ay, By, Cy and Dy is at least 2; and where M is a metal.

Metal M may be selected from all of the main group metals and transitionmetals may to be complexed with the N-heterocyclic carbene substitutedporphyrin and porphyrinoid ligands to form metal complexes.Additionally, isotopes of the main group metals and transition metalsmay be complexed with the ligands of the present invention to providesmetal complexes.

While the known doubly N-confused porphyrins form neutral metalcomplexes with metals in +2 and +3 oxidation states, the carbeneporphyrins, carbene porphyrinoids, expanded carbeneporphyrins andexpanded carbeneporphyrinoids have the capability of forming neutralmetal complexes with metals in the 0, +1, +2, +3, +4, and +5 oxidationstates. Because of the strong complexing ability of N-heterocycliccarbenes, the compositions of the present invention, thecarbeneporphyrins and expanded carbeneporphyrins, bind more strongly tothe central metal atom in comparison to porphyrins and confusedporphyrins without substitution with N-heterocyclic carbene groups.

The N-heterocyclic carbene porphyrins, including the N-heterocycliccarbene porphyrinoids, and the expanded N-heterocyclic carbeneporphyrins, including the expanded N-heterocyclic carbene porphyrinoids,of the present invention may be complexed with metal atoms to formligand-metal complexes. Virtually of the of the main group metals andtransition metals may be complexed with the N-heterocyclic carbeneporphyrins, including the N-heterocyclic carbene porphyrinoids, and theexpanded N-heterocyclic carbene porphyrins, including the expandedN-heterocyclic carbene porphyrinoids, of the present invention to formligand-metal complexes.

Suitable metal atoms, M, that may be complexed with the N-heterocycliccarbene porphyrins and N-heterocyclic carbene porphyrinoids of thepresent invention include, but are not limited to, all group IIA metals,group IIA metals, group IIIA metals, group IVA metals, group VA metals,group VIA metals, group VIIA metals, and group VIIIA metals. The groupIVB metals Si, Ge, SN and Pb may be complexed with the N-heterocycliccarbene porphyrins and N-heterocyclic carbene porphyrinoids to formligand-metal complexes. The group VB metals P, As, Sb and Bi may becomplexed with N-heterocyclic carbene porphyrins and N-heterocycliccarbene porphyrinoids to form ligand-metal complexes. The group VIBmetals Te and Po may be complexed with N-heterocyclic carbene porphyrinsand N-heterocyclic carbene porphyrinoids to form ligand-metal complexes.The group VIIB metal At may be complexed with N-heterocyclic carbeneporphyrins and N-heterocyclic carbene porphyrinoids to form ligand-metalcomplexes. Additionally, the lanthanides and the actinides may becomplexed with the N-heterocyclic carbene porphyrins and N-heterocycliccarbene porphyrinoids of the present invention to form ligand-metalcomplexes.

Preferably, the metals that may be used to form metal complexes with theligands include those metals that have particular application in MRI,PET and PDT. These metals include, but are not limited to, Be(II),Mg(II), Ca(II), Sr(II), Ba(II), B(III), Al(III), Ga(III), In(III),Cr(O), Fe(O), Ni(O), Mo(O), Ru(O), Pd(O), Pt(O), Re(I), Cr(I), Mn(I),Fe(I), Co(I), Ni(I), Cu(I), Rh(I), Ag(I), Re(I), Ir(I), Au(I), V(I),Cr(II), Fe(II), Co(II), Ir(III), Ti(IV), V(IV), Zr(IV), Nb(IV), Hf(IV),Ta(IV), Mo(IV), W(VI), Re(VII), La(II), La(III), Nd(III), Sm(II),Er(III), Sm(II) and Yb(II). Suitable examples of these metals havingparticular application in MRI and are, therefore, useful in the presentinvention include, but are not limited to, Fe(III), Mg(II), Mn(II), andGd(III). More preferably, Gd(III) will be used to form ligand-metalcomplexes that find particular use in MRI applications. Usefulradioisotopes that can be complexed with the N-heterocylic carbenesubstituted porphyrins and porphyrinoids in clued, but are not limitedto, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹⁷Sn, ¹⁸⁶Re, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho and ¹⁷⁷Lu.¹¹¹Ag is a preferred radioisotope that can be complexed with theN-heterocyclic carbenes substituted ligands of the present invention.

The present invention also provides processes for the preparation for ofthe N-heterocyclic carbene substituted porphyrins and N-heterocycliccarbene substituted porphyrinoids of the present invention, includingthe preparation of N-heterocyclic carbene substituted expandedporphyrins and N-heterocyclic carbene substituted expandedporphyrinoids.

The present invention further provides a process for the preparation ofa complex of the ligands of the present invention with a desired metalto produce a ligand-metal complex.

Preparation of N-heterocyclic Carbene Porphyrins and Porphyrinoids

The following examples are set forth to describe the preparation of thecompositions of the present invention in further detail and toillustrate the methods of the present invention. However, the examplesshould not be construed as limiting the present invention in any manner.

In the following synthetic procedures the synthesis of the ligands ofthe present invention is described. However, ligands can be synthesizedwith various functional groups on the exterior of the rings in order togive the overall complex sufficient solubility, lipophilicity andtargeting properties. Pyrroles and imidazoles serve as the fundamentalbuilding blocks in the procedures discussed below.

Synthesis of Monocarbeneporphyrin

Below is a reaction scheme for the synthesis of mono N-heterocycliccarbene substituted porphyrin:

Synthesis of Dicarbeneporphyrinoids

Below is a reaction scheme for the synthesis of di N-heterocycliccarbene substituted porphyrinoids:

Synthesis of Tricarbeneporphyrinoids

Below is a reaction scheme for the synthesis of tricarbeneporphyrinoidsand ligand-metal complexes of tricarbeneporphyrinoids and a metal:

Synthesis of Tetracarbeneporphyrinoids

Below is a reaction scheme for the synthesis oftetracarbeneporphyrinoids and ligand-metal complexes oftetracarbeneporphyrinoids and a metal:

Synthesis of Carbene Corrole Porphyrins

Below is a reaction scheme for the synthesis of carbene corroleporphyrins and ligand-metal complexes of carbene corrole porphyrins anda metal:

Synthesis of Expanded Monocarbenepentaphyrin

Below is a reaction scheme for the synthesis of mono N-heterocyliccarbene substituted expanded porphyrin:

Synthesis of Dicarbenepentaphyrin

Below is a reaction scheme for the synthesis of di-N-heterocylic carbenesubstituted expanded porphyrin:

It should be noted that the term “N-heterocyclic carbene porphyrin”refers to porphyrins that have at least one pyrrole group replaced by aN-heterocyclic carbene and having unsaturated bonds linking the groupsof the ring together or a mixture of saturated and unsaturated bondslinking the group of the ring together. The term “N-heterocyclic carbeneporphyrinoid” refers to porphyrins that have at least one pyrrole groupreplaced by a N-heterocyclic carbene group and having saturated bondslinking the groups of the ring together.

In other embodiments, the N-heterocyclic carbene substituted porphyrinsand porphyrinoids and metal complexes of the N-heterocyclic carbenesubstituted porphyrins and porphyrinoids may be further linked or bondedto a targeting moiety via a linker group. The targeting moiety may beselected to be specific to a receptor or protein located on a targettissue or cell. The targeting moiety further enables the ligand-metalcomplexes of the present invention to target specific tissue fordiagnosis and treatment. In an alternative embodiment, the linker groupand targeting moiety are dissociative, which enables the ligand-metalcomplex to diffuse out of the target tissue or cells and be removed fromthe patient's body.

Preparation of N-heterocyclic Carbene Porphyrins with Targeting Moiety

Below are reaction schemes for the synthesis of N-heterocyclic carbenesubstituted porphyrins having a targeting moiety bonded thereto:

The targeting moiety is bonded to the N-heterocyclic carbene substitutedporphyrin via a linker group. The linker group can be any organic groupincluding, for example, organic radical groups and polymers. Suitableorganic groups include alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,arylalkyl, alkylaryl, alkoxy, amines, amides, and polyethers. Thetargeting moiety can be selected in order to optimize the solubility andlipophilicity of.

The N-heterocyclic carbene substituted ligands of the present invention,including the N-heterocyclic carbene substituted porphyrins andporphyrinoids, possess cavity sizes and chelating properties that enablethe ligands to bind metal atoms more stringly than those macrocyclesknown in the prior art. The ability of the ligands of the presentinvention to bind more strongly to the metal atoms helps overcome theproblems of dissociation of metal from the ligand while the metalcomplex is in a patient's body. As such, the ligands and metal complexesof the invention can be utilized as radioimaging agents and therapeuticradiopharmaceuticals for treating, for example, cancer. The metalcomplexes of the present invention can be used to recognizetumor-associated antigens and tumor specific antigens to deliver atherapeutic and cytotoxic agent to cancerous tissue and cells, whileminimizing exposure of the cytotoxic agents to non-cancerous, healthytissue and cells. Antibodies such as, for example, monoclonal antibodiesthat recognize tumor associated antigen or tumor specific antigen, arecomplexed with strepravidin and infused into a patient. The antibodyrecognizes the tumor associated antigen and associates with is, therebylocalizing the streptavidin in the tumor tissue. Subsequently, the metalcomplexes of N-heterocyclic carbene substituted porphyrins orporphyrinoid, which have biotin bound thereto, are infused into thepatient. The streptavidin binds the biotin and localizes theradionucleotide at the tumor tissue.

Based on the foregoing disclosure, it is therefore demonstrated that theobjects of the present invention are accomplished by the N-heterocycliccarbene porphyrins and porphyrinoids described and processes forinstallation described herein. It should be appreciated that the presentinvention is not limited to the specific embodiments described above,but includes variations, modifications and equivalent embodiments.

1. A composition of matter comprising a N-heterocylic carbenesubstituted porphyrin.
 2. The composition of claim 1, wherein saidN-heterocylic carbene substituted porphyrin has the following generalformula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy.
 3. The composition of matter of claim 2, wherein each of R₁-R₁₁contains from 1 carbon atom to about 10 carbon atoms.
 4. The compositionof claim 3, wherein each of R₁-R₁₁ contains from 1 carbon atom to about6 carbon atoms.
 5. The composition of matter of claim 1, wherein saidN-heterocylic carbene substituted porphyrin has the following generalformula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy; wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may behydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy.
 6. Thecomposition of matter of claim 5, wherein each of R₁-R₁₄ contains from 1carbon atom to about 10 carbon atoms.
 7. The composition of claim 6,wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6 carbonatoms.
 8. The composition of claim 1, wherein the N-heterocylic carbenesubstituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, wherein Ay, By, Cy and Dy is 1 or greater with the proviso thatat least one of Ay, By, Cy and Dy is at least
 2. 9. The composition ofmatter of claim 8, wherein each of R₁-R₁₁ contains from 1 carbon atom toabout 10 carbon atoms.
 10. The composition of claim 9, wherein each ofR₁-R₁₁ contains from 1 carbon atom to about 6 carbon atoms.
 11. Thecomposition of claim 1, wherein the N-heterocylic carbene substitutedporphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, wherein Ay, By, Cy and Dy is 1 or greater with the proviso thatat least one of Ay, By, Cy and Dy is at least 2; and wherein x may beCR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogen and organicgroups including alkyl, cyclo alkyl, substituted cycloalkyl, alkenyl,cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl, substituted aryl,arylalkyl, alkylaryl, and alkoxy.
 12. The composition of matter of claim11, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 10carbon atoms.
 13. The composition of claim 12, wherein each of R₁-R₁₄contains from 1 carbon atom to about 6 carbon atoms.
 14. A metal complexcomprising: a N-heterocylic carbene substituted porphyrin; and at leastone metal atom bonded to N-heterocylic carbene substituted porphyrin.15. The metal complex of claim 14, wherein said metal complex has thefollowing general formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy; and where M is a metal.
 16. The metal complex of claim 15,wherein each of R₁-R₁₁ contains from 1 carbon atom to about 10 carbonatoms.
 17. The metal complex of claim 16, wherein each R₁-R₁₁ containsfrom 1 carbon atom to about 6 carbon atoms.
 18. The metal complex ofclaim 14, wherein said metal atom is selected from the group consistingof IIA metals, group IIA metals, group IIIA metals, group IVA metals,group VA metals, group VIA metals, group VIIA metals, and group VIIIAmetals, group IVB metals, group VB metals, group VIB metals, VIIBmetals, lanthanides and actinides.
 19. The metal complex of claim 18,wherein the group IVB metals are selected from the group consisting ofSi, Ge, SN and Pb.
 20. The metal complex of claim 18, wherein the groupVIB metals are selected from the group consisting of Te and Po.
 21. Themetal complex of claim 18, wherein the group VB metals are selected fromthe group consisting of P, As, Sb and Bi.
 22. The metal complex of claim18, wherein the group VIIB metal is At.
 23. The metal complex of claim18, wherein the metal atom is Ag.
 24. The metal complex of claim 18,wherein the metal atom is Gd.
 25. The metal complex of claim 14, whereinsaid N-heterocylic carbene substituted porphyrin has the followinggeneral formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy; wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may behydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy; and wherein Mis a metal.
 26. The composition of matter of claim 25, wherein each ofR₁-R₁₄ contains from 1 carbon atom to about 10 carbon atoms.
 27. Thecomposition of claim 26, wherein each of R₁-R₁₄ contains from 1 carbonatom to about 6 carbon atoms.
 28. The metal complex of claim 25, whereinsaid metal atom is selected from the group consisting of IIA metals,group IIA metals, group IIIA metals, group IVA metals, group VA metals,group VIA metals, group VIIA metals, and group VIIIA metals, group IVBmetals, group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 29. The metal complex of claim 28, wherein the group IVBmetals are selected from the group consisting of Si, Ge, SN and Pb. 30.The metal complex of claim 28, wherein the group VIB metals are selectedfrom the group consisting of Te and Po.
 31. The metal complex of claim28, wherein the group VB metals are selected from the group consistingof P, As, Sb and Bi.
 32. The metal complex of claim 28, wherein thegroup VIIB metal is At.
 33. The metal complex of claim 28, wherein themetal atom is Ag.
 34. The metal complex of claim 28, wherein the metalatom is Gd.
 35. The metal complex of claim 14, wherein the N-heterocyliccarbene substituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, wherein Ay, By, Cy and Dy is 1 or greater with the proviso thatat least one of Ay, By, Cy and Dy is at least 2; and wherein M is ametal.
 36. The metal complex of claim 35, wherein each of R₁-R₁₁contains from 1 carbon atom to about 10 carbon atoms.
 37. The metalcomplex of claim 36, wherein each of R₁-R₁₁ contains from 1 carbon atomto about 6 carbon atoms.
 38. The metal complex of claim 35, wherein saidmetal atom is selected from the group consisting of IIA metals, groupIIA metals, group IIIA metals, group IVA metals, group VA metals, groupVIA metals, group VIIA metals, and group VIIIA metals, group IVB metals,group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 39. The metal complex of claim 35, wherein the group IVBmetals are selected from the group consisting of Si, Ge, SN and Pb. 40.The metal complex of claim 35, wherein the group VIB metals are selectedfrom the group consisting of Te and Po.
 41. The metal complex of claim35, wherein the group VB metals are selected from the group consistingof P, As, Sb and Bi.
 42. The metal complex of claim 35, wherein thegroup VIIB metal is At.
 43. The metal complex of claim 35, wherein themetal atom is Ag.
 44. The metal complex of claim 35, wherein the metalatom is Gd.
 45. The metal complex of claim 14, wherein the N-heterocyliccarbene substituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, wherein Ay, By, Cy and Dy is 1 or greater with the proviso thatat least one of Ay, By, Cy and Dy is at least 2; wherein x may be CR₁₂or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogen and organic groupsincluding alkyl, cyclo alkyl, substituted cycloalkyl, alkenyl,cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl, substituted aryl,arylalkyl, alkylaryl, and alkoxy; and wherein M is a metal.
 46. Themetal complex of claim 45, wherein each of R₁-R₁₄ contains from 1 carbonatom to about 10 carbon atoms.
 47. The metal complex of claim 45,wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6 carbonatoms.
 48. The metal complex of claim 45, wherein said metal atom isselected from the group consisting of IIA metals, group IIA metals,group IIIA metals, group IVA metals, group VA metals, group VIA metals,group VIIA metals, and group VIIIA metals, group IVB metals, group VBmetals, group VIB metals, VIIB metals, lanthanides and actinides. 49.The metal complex of claim 46, wherein the group IVB metals are selectedfrom the group consisting of Si, Ge, SN and Pb.
 50. The metal complex ofclaim 46, wherein the group VIB metals are selected from the groupconsisting of Te and Po.
 51. The metal complex of claim 46, wherein thegroup VB metals are selected from the group consisting of P, As, Sb andBi.
 52. The metal complex of claim 46, wherein the group VIIB metal isAt.
 53. The metal complex of claim 46, wherein the metal atom is Ag. 54.The metal complex of claim 46, wherein the metal atom is Gd.
 55. Acomposition of matter comprising: a N-heterocylic carbene substitutedporphyrin; at least one metal atom bonded to said N-heterocylic carbenesubstituted porphyrin; and a targeting moiety bonded to saidN-heterocylic carbene substituted porphyrin.
 56. The composition ofmatter of claim 55, wherein said N-heterocylic carbene substitutedporphyrin has the following general formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy.
 57. The composition of matter of claim 56, wherein each ofR₁-R₁₁ contains from 1 carbon atom to about 10 carbon atoms.
 58. Thecomposition of matter of claim 57, wherein each of R₁-R₁₁ contains from1 carbon atom to about 6 carbon atoms.
 59. The composition of matter ofclaim 56, wherein said metal atom is selected from the group consistingof IIA metals, group IIA metals, group IIIA metals, group IVA metals,group VA metals, group VIA metals, group VIIA metals, and group VIIIAmetals, group IVB metals, group VB metals, group VIB metals, VIIBmetals, lanthanides and actinides.
 60. The composition of matter ofclaim 59, wherein the group IVB metals are selected from the groupconsisting of Si, Ge, SN and Pb.
 61. The composition of matter of claim59, wherein the group VIB metals are selected from the group consistingof Te and Po.
 62. The composition of matter of claim 59, wherein thegroup VB metals are selected from the group consisting of P, As, Sb andBi.
 63. The composition of matter of claim 59, wherein the group VIIBmetal is At.
 64. The composition of matter of claim 59, wherein themetal atom is Ag.
 65. The composition of matter of claim 59, wherein themetal atom is Gd.
 66. The composition of matter of claim 55, whereinsaid N-heterocylic carbene substituted porphyrin has the followinggeneral formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ maybe hydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy.
 67. Thecomposition of matter of claim 66, wherein each of R₁-R₁₄ contains from1 carbon atom to about 10 carbon atoms.
 68. The composition of matter ofclaim 67, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6carbon atoms.
 69. The composition of matter of claim 66, wherein saidmetal atom is selected from the group consisting of IIA metals, groupIIA metals, group IIIA metals, group IVA metals, group VA metals, groupVIA metals, group VIIA metals, and group VIIIA metals, group IVB metals,group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 70. The composition of matter of claim 69, wherein the groupIVB metals are selected from the group consisting of Si, Ge, SN and Pb.71. The composition of matter of claim 69, wherein the group VIB metalsare selected from the group consisting of Te and Po.
 72. The compositionof matter of claim 69, wherein the group VB metals are selected from thegroup consisting of P, As, Sb and Bi.
 73. The composition of matter ofclaim 69, wherein the group VIIB metal is At.
 74. The composition ofmatter of claim 69, wherein the metal atom is Ag.
 75. The composition ofmatter of claim 69, wherein the metal atom is Gd.
 76. The composition ofmatter of claim 55, wherein the N-heterocylic carbene substitutedporphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, wherein Ay, By, Cy and Dy is 1 or greater with the proviso thatat least one of Ay, By, Cy and Dy is at least
 2. 77. The composition ofmatter of claim 76, wherein each of R₁-R₁₁ contains from 1 carbon atomto about 10 carbon atoms.
 78. The composition of matter of claim 77,wherein each of R₁-R₁₁ contains from 1 carbon atom to about 6 carbonatoms.
 79. The composition of matter of claim 76, wherein said metalatom is selected from the group consisting of IIA metals, group IIAmetals, group IIIA metals, group IVA metals, group VA metals, group VIAmetals, group VIIA metals, and group VIIIA metals, group IVB metals,group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 80. The composition of matter of claim 79, wherein the groupIVB metals are selected from the group consisting of Si, Ge, SN and Pb.81. The composition of matter of claim 79, wherein the group VIB metalsare selected from the group consisting of Te and Po.
 82. The compositionof matter of claim 79, wherein the group VB metals are selected from thegroup consisting of P, As, Sb and Bi.
 83. The composition of matter ofclaim 79, wherein the group VIIB metal is At.
 84. The composition ofmatter of claim 79, wherein the metal atom is Ag.
 85. The composition ofmatter of claim 79, wherein the metal atom is Gd.
 86. The composition ofmatter of claim 55, wherein the N-heterocylic carbene substitutedporphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas, with the proviso that at least one of A-D isN-heterocyclic carbene:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, wherein Ay, By, Cy and Dy is 1 or greater with the proviso thatat least one of Ay, By, Cy and Dy is at least 2; and wherein x may beCR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may be hydrogen and organicgroups including alkyl, cyclo alkyl, substituted cycloalkyl, alkenyl,cycloalkenyl, substitute cycloalkenyl, alkynyl, aryl, substituted aryl,arylalkyl, alkylaryl, and alkoxy.
 87. The composition of matter of claim86, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 10carbon atoms.
 88. The composition of matter of claim 87, wherein each ofR₁-R₁₄ contains from 1 carbon atom to about 6 carbon atoms.
 89. Thecomposition of matter of claim 86, wherein said metal atom is selectedfrom the group consisting of IIA metals, group IIA metals, group IIIAmetals, group IVA metals, group VA metals, group VIA metals, group VIIAmetals, and group VIIIA metals, group IVB metals, group VB metals, groupVIB metals, VIIB metals, lanthanides and actinides.
 90. The compositionof matter of claim 89, wherein the group IVB metals are selected fromthe group consisting of Si, Ge, SN and Pb.
 91. The composition of matterof claim 89, wherein the group VIB metals are selected from the groupconsisting of Te and Po.
 92. The composition of matter of claim 89,wherein the group VB metals are selected from the group consisting of P,As, Sb and Bi.
 93. The composition of matter of claim 89, wherein thegroup VIIB metal is At.
 94. The composition of matter of claim 89,wherein the metal atom is Ag.
 95. The composition of matter of claim 89,wherein the metal atom is Gd.
 96. The composition of claim 55, whereinthe targeting moiety is selected form the group consisting of biotin andnitroimidazoles.
 97. The composition of claim 55, wherein said linker isselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, arylalkyl, alkylaryl, alkoxy, amines, amides, and polyethers.